Abstract
Glycogen synthase kinase-3 (GSK-3)-α and -β are closely related protein-serine kinases, which act as inhibitory components of Wnt signalling during embryonic development and cell proliferation in adult tissues1,2. Insight into the physiological function of GSK-3 has emerged from genetic analysis in Drosophila3,4, Dictyostelium 5 and yeast6,7. Here we show that disruption of the murine GSK-3β gene results in embryonic lethality caused by severe liver degeneration during mid-gestation, a phenotype consistent with excessive tumour necrosis factor (TNF) toxicity, as observed in mice lacking genes involved in the activation of the transcription factor activation NF-κB. GSK-3β-deficient embryos were rescued by inhibition of TNF using an anti-TNF-α antibody. Fibroblasts from GSK-3β-deficient embryos were hypersensitive to TNF-α and showed reduced NF-κB function. Lithium treatment (which inhibits GSK-3; refs 8, 9) sensitized wild-type fibroblasts to TNF and inhibited transactivation of NF-κB. The early steps leading to NF-κB activation (degradation of I-κB and translocation of NF-κB to the nucleus) were unaffected by the loss of GSK-3β, indicating that NF-κB is regulated by GSK-3β at the level of the transcriptional complex. Thus, GSK-3β facilitates NF-κB function.
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References
Welsh, G. I., Wilson, C. & Proud, C. G. GSK-3: a SHAGGY frog story. Trends Cell Biol. 6, 274–279 ( 1996).
Dale, T. C. Signal transduction by the Wnt family of ligands. Biochem. J. 239, 209–223 (1998).
Siegfried, E., Perkins, L. A., Capaci, T. M. & Perrimon, N. Putative protein kinase product of the Drosophila segment-polarity gene zeste-white3. Nature 345, 825– 829 (1990).
Ruel, L., Bourouis, M., Heitzler, P., Pantesco, V. & Simpson, P. Drosophila shaggy kinase and rat glycogen synthase kinase-3 have conserved activities and act downstream of Notch. Nature 362, 557– 560 (1993).
Harwood, A. J., Plyte, S. E., Woodgett, J., Strutt, H. & Kay, R. R. Glycogen synthase kinase 3 regulates cell fate in Dictyostelium. Cell 80, 139–148 (1995).
Puziss, J. W., Hardy, T. A., Johnson, R. B., Roach, P. J. & Hieter, P. MDS1, a dosage suppressor of an mck1 mutant, encodes a putative yeast homolog of glycogen synthase kinase 3. Mol. Cell. Biol. 14, 831–839 (1994).
Plyte, S. E., Feoktistova, A., Burke, J. D., Woodgett, J. R. & Gould, K. L. Schizosaccharomyces pombe skp1+ encodes a protein kinase related to mammalian glycogen synthase kinase 3 and complements a cdc14 cytokinesis mutant. Mol. Cell. Biol. 16, 179–191 ( 1996).
Klein, P. S. & Melton, D. A. A molecular mechanism for the effect of lithium on development. Proc. Natl Acad. Sci. USA 93, 8455–8459 (1996).
Stambolic, V., Ruel, L. & Woodgett, J. R. Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells. Curr. Biol. 6, 1664–1668 (1996).
He, X., Saint-Jeannet, J. P., Woodgett, J. R., Varmus, H. E. & Dawid, I. B. Glycogen synthase kinase-3 and dorsoventral patterning in Xenopus embryos. Nature 374, 617–622 (1995).
Dominguez, I., Itoh, K. & Sokol, S. Y. Role of glycogen synthase kinase 3 beta as a negative regulator of dorsoventral axis formation in Xenopus embryos. Proc. Natl Acad. Sci. USA 92, 8498– 8502 (1995).
Nasevicius, A. et al. Evidence for a frizzled-mediated wnt pathway required for zebrafish dorsal mesoderm formation. Development 125 , 4293–4992 (1998).
Li, Q., Van Antwerp, D., Mercurio, F., Lee, K. F. & Verma, I. M. Severe liver degeneration in mice lacking the IκB kinase 2 gene. Science 284, 321–325 (1999).
Li, Z. W. et al. The IKKβ subunit of IκB kinase (IKK) is essential for nuclear factor κB activation and prevention of apoptosis. J. Exp. Med. 189, 1839–1845 (1999).
Beg, A. A., Sha, W. C., Bronson, R. T., Ghosh, S. & Baltimore, D. Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-κB. Nature 376, 167–170 ( 1995).
Yeh, W. C. et al. Early lethality, functional NF-κB activation, and increased sensitivity to TNF-induced cell death in TRAF2-deficient mice. Immunity 7, 715–725 ( 1997).
Beyaert, R., Vanhaesebroeck, B., Suffys, P., Van Roy, F. & Fiers, W. Lithium chloride potentiates tumor necrosis factor-mediated cytotoxicity in vitro and in vivo. Proc. Natl Acad. Sci. USA 86, 9494– 9498 (1989).
Beg, A. A. & Baltimore, D. An essential role for NF-κB in preventing TNF-α-induced cell death. Science 274, 782–784 (1996).
Van Antwerp, D. J., Martin, S. J., Kafri, T., Green, D. R. & Verma, I. M. Suppression of TNF-α-induced apoptosis by NF-κB. Science 274, 787–789 (1996).
Wang, C. Y., Mayo, M. W. & Baldwin, A. S. TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-κB. Science 274, 784–787 (1996).
Liu, Z. G., Hsu, H., Goeddel, D. V. & Karin, M. Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-κB activation prevents cell death. Cell 87 , 565–576 (1996).
Baueuerle, P. A. & Baltimore, D. IκB: a specific inhibitor of the NF-κB transcription factor. Science 242, 540–546 ( 1988).
Oliver, F. J. et al. Resistance to endotoxic shock as a consequence of defective NF-κB activation in poly (ADP-ribose) polymerase-1 deficient mice. EMBO J. 18, 4446–4454 ( 1999).
Beraud, C., Henzel, W. J. & Baeuerle, P. A. Involvement of regulatory and catalytic subunits of phosphoinositide 3-kinase in NF-κB activation. Proc. Natl Acad. Sci. USA 96, 429–434 (1999).
Kane, L. P., Shapiro, V. S., Stokoe, E. & Weiss, A. Induction of NF-κB by the Akt/PKB kinase. Curr. Biol. 9, 601–604 (1999).
Romashkova, J. A. & Makarov, S. S. NF-κB is a target of AKT in anti-apoptotic PDGF signalling. Nature 401, 86–90 (1999).
Ozes, O. N. et al. NF-κB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 401, 82–85 (1999).
Sizemore, N., Leung, S. & Stark, G. R. Activation of phosphatidylinositol 3-kinase in response to interleukin-1 leads to phosphorylation and activation of the NF-κB p65/RelA subunit. Mol. Cell. Biol. 19, 4798 –4805 (1999).
Cross, D. A., Alessi, D. R., Cohen, P., Andjelkovich, M. & Hemmings, B. A. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378, 785–789 (1995).
Wijsman, J. H. et al. A new method to detect apoptosis in paraffin sections: in situ end-labeling of fragmented DNA. J. Histochem. Cytochem. 41, 7–12 (1993 ).
Acknowledgements
We thank W.-C. Yeh for the TRAF2-deficient mouse EFs and C. Mirtsos, M. Bonnard, T. Nicklee, A. Ali, M. Parsons, T. Mak, D. Wakeham and A. Shahinian for technical help and advice. K.P.H. is supported by a Medical Research Council of Canada Studentship. J.R.W. is supported by grants from the Medical Research Council and Howard Hughes Medical Institute and is a Medical Research Council Senior Scientist.
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Hoeflich, K., Luo, J., Rubie, E. et al. Requirement for glycogen synthase kinase-3β in cell survival and NF-κB activation. Nature 406, 86–90 (2000). https://doi.org/10.1038/35017574
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DOI: https://doi.org/10.1038/35017574
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